Journal of Ethnopharmacology 107 (2006) 53–58

Antidepressant and anxiolytic effects of hydroalcoholic extractfrom Salvia elegans�

Maribel Herrera-Ruiz a,∗, Yolanda Garcıa-Beltran a, Sergio Mora b, Gabriela Dıaz-Veliz b,Glauce S.B. Viana c, Jaime Tortoriello a, Guillermo Ramırez a,∗

a Centro de Investigacion Biomedica del Sur, IMSS. Argentina 1, Xochitepec, Morelos 62790, Mexicob Laboratorio de Farmacologıa del Comportamiento, Programa de Farmacologıa Molecular y Clınica, Instituto de Ciencias Biomedicas,

Facultad de Medicina, Universidad de Chile, Santiago, Chilec Universidade Federal do Ceara, Faculdade Medicina, Departamento de Fisiologia y Farmacologıa, Brazil

Received 31 October 2005; received in revised form 16 January 2006; accepted 2 February 2006Available online 28 February 2006

Abstract

Salvia elegans Vahl (Lamiaceae), popularly known as “mirto”, is a shrub that has been widely used in Mexican traditional medicine for thetshtmea©

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reatment of different central nervous system (CNS) diseases, principally, anxiety. Nevertheless, the available scientific information about thispecies is scarce and there are no reports related to its possible effect on the CNS. In this work, the antidepressant and anxiolytic like effects ofydroalcoholic (60%) extract of Salvia elegans (leaves and flowers) were evaluated in mice. The extract, administered orally, was able to increasehe percentage of time spent and the percentage of arm entries in the open arms of the elevated plus-maze, as well as to increase the time spent by

ice in the illuminated side of the light–dark test, and to decrease the immobility time of mice subjected to the forced swimming test. The samextract was not able to modify the spontaneous locomotor activity measured in the open field test. These results provide support for the potentialntidepressant and anxiolytic activity of Salvia elegans.

2006 Elsevier Ireland Ltd. All rights reserved.

eywords: Anxiety; Depression; Salvia elegans; Elevated plus-maze; Forced swimming test; Open field

. Introduction

According to the World Health report (WHO, 2001), approx-mately 450 million people suffer from a mental or behavioralisorder, yet only a small minority of them receive even theost basic treatment. This amounts to 12.3% of the global bur-

en of disease, and will rise to 15% by 2020 (Reynolds, 2003).n the search for new therapeutic products for the treatmentf neurological disorders, medicinal plant research, worldwide,as progressed constantly, demonstrating the pharmacological

Abbreviations: CNS, central nervous system; DZP, diazepam; EPM, elevatedlus maze; FST, forced swimming test; IMI, imipramine; LDT, light–dark test;FT, open field test; PTX, pycrotoxine

� This work was part of the M.Sc. Thesis of Y.G.B. Facultad de Medicina,niversidad Autonoma del Estado de Morelos, Mexico, 2005.∗ Corresponding authors. Tel.: +52 777 3 61 21 55; fax: +52 777 3 61 21 55.

E-mail addresses: cibis herj@yahoo.com.mx (M. Herrera-Ruiz),moramirez@yahoo.com (G. Ramırez).

effectiveness of different plant species in a variety of animalmodels (Zhang, 2004).

In Mexican traditional medicine, an infusion is prepared fromthe leaves and flowers of Salvia elegans Vahl (Lamiaceae), popu-larly known as “mirto”, and administered orally for treating CNSdiseases. This plant constitutes one of the most used species inMexico for the treatment of anxiety, and insomnia (Aguilar et al.,1994). It is important to mention that the common name of thisplant is shared with other members of the genus (Martınez, 1979;Bello, 1993). Despite the widely popular use of the plant, it wasnot possible to find pharmacological data confirming some activ-ity of this plant on the mentioned diseases. The only evidenceof probable CNS activity was found in a report showing that themethanolic extract of Salvia elegans was able to displace [3H]-(N)-scopolamine from muscarinic receptors in homogenates ofhuman cerebral cortical cell membranes (Wake et al., 2000).Despite the scarce pharmacological scientific information aboutthis species, there are other members of the family which pos-sess demonstrated CNS activities. Salvia divinorium Epling and

378-8741/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.

oi:10.1016/j.jep.2006.02.003

54 M. Herrera-Ruiz et al. / Journal of Ethnopharmacology 107 (2006) 53–58

Jativa has hallucinogenic (Siebert, 1994; Chavkin et al., 2004)and antidepressant properties (Hanes, 2001), and Salvia offici-nalis L. possesses metabolites with benzodiazepine-like effects(Kavvadias et al., 2003), Salvia miltiorrhiza f. alba Wu and Li,used in Chinese traditional medicine, has shown neuroprotec-tive effect, due to the NMDA receptor antagonistic activity (Sunet al., 2003), and Salvia reuterana Boiss recently showed anxi-olytic effect in mice (Rabbani et al., 2005).

Twenty-eight volatile constituents were identified in essen-tial oil from Salvia elegans, mono- and sesqui- terpenoids suchas trans-ocimene, linalool, �-caryophyllene, germacrene D andspathulenol, aliphatic alcohols such as 2-propanol and 3-octanol,and trans-3-hexenal (Makino et al., 1996).

These data confirm that different members of the Lamiaceaefamily are able to modulate the physiology of the CNS. On thisbasis, the objective of the present study was to evaluate the anxi-olytic and antidepressant effect produced by the hydroalcoholicextract from Salvia elegans in mice. Experiments were con-ducted with the ICR mice strain, which permits the analysis ofthe effects produced by Salvia elegans in different mice models.

2. Methods

2.1. Plant material and extract preparation

Leaves and flowers of Salvia elegans were collected fromtiHirareMf#wtu(l

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Society for Neuroscience (USA). The experimental protocolwas approved by the Institutional Research Committee. Theminimum number of animals and duration of observationrequired to obtain consistent data were employed.

Male ICR mice (32–38 g) purchased at Harlan Mexico wereused. All animals were maintained under controlled conditionsof temperature (22 ± 2 ◦C), and illumination (12 h light–darkcycle), with free access to food (Harlan rodent lab diet) andwater. Groups of eight animals were organized and, in order toreduce the influence of day variation, all assays were conductedfrom 8 to 13 h, in a special noise-free room with controlled illu-mination.

Mice were treated orally with different doses of the hydroal-coholic extract of Salvia elegans (125, 250, 500, 1000 and2000 mg/kg). A negative control group was included whichreceived physiological saline solution (p.o.). Positive controlgroups were administered with 15 mg/kg of IMI i.p. (for forcedswimming test) or with 1.0 mg/kg of DZP i.p. (for the othertests) and an anxiogenic group was treated with 2.0 mg/kgof PTX i.p. (for elevated plus-maze, light–dark test and openfield test). All treatments were administered 1 h before the test,with the exception of forced swimming test, in which IMIand the plant extract were administered 24, 18 and 1 h beforethe test.

2.4. Elevated plus-maze (EPM)

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he state of Puebla, south west of Mexico. Plant material wasdentified by Abigail Aguilar-Contreras, M.Sc., the IMSSMerbarium Director (located in National Medical Center, Mex-

co City). Voucher specimens were stored at this site for futureeference (IMSSM-14588). From the collected plant, the leavesnd flowers were selected and dried under dark conditions atoom temperature for 2 weeks. Dry material was milled in anlectrical grinder (Pulvex) obtaining particles less than 4 mm.illed material was extracted in 60% ethanol solution at 50 ◦C

or 2 h. Afterwards, the extract was filtered through a Wattman1 paper and extracted once again (under the same conditions)ith a new solvent. The obtained extracts were reunited and

he solvent was evaporated to dryness with a rotary evaporatornder reduced pressure. The yield of the extract was quantified16.48%) and the obtained material was protected from directight and stored under 4 ◦C until its use.

.2. Drugs

The hydroalcoholic extract from Salvia elegans was useds experimental extract (25–2000 mg/kg; dissolved in salineolution), and as positive controls were used: diazepam (DZP,.0 mg/kg, Sigma) as an anxiolytic drug; picrotoxin (PTX,.0 mg/kg, Sigma St. Louis, USA) as an anxiogenic drug; andmipramine hydrochloride (IMI, 15 mg/kg, Sigma St. Louis,SA) as an antidepressant drug.

.3. Animals and treatments

All experiments were conducted in accordance with inter-ational standards of animal welfare recommended by the

This test has been widely validated to measure anxietyn rodents (Pellow et al., 1985; Lister, 1987). This appa-atus was made of Plexiglas and consisted of two openrms (30 cm × 5 cm) and two closed arms (30 cm × 5 cm) with5 cm walls. The arms extended from a central platform5 cm × 5 cm). The maze was elevated 38.5 cm from the roomoor.

Each animal was placed at the center of the maze, facing onef the enclosed arms. Number of entries and the time spent innclosed and open arms was recorded for 5 min test. Entry inton arm was defined as the animal placing all four paws onto therm. All tests were taped by using a video camera. After eachest, the maze was carefully cleaned up with a wet tissue paper10% ethanol solution).

.5. Forced swimming test (FST)

The FST is the most widely used pharmacological in vivoodel for assessing antidepressant activity (Porsolt et al., 1977).he development of immobility when the mice are placed in an

nescapable cylinder filled with water, reflects the cessation ofersistent escape-directed behavior (Lucki, 1997). The appara-us consisted of a clear plexiglas cylinder (20 cm high × 12 cmiameter) filled to a 15 cm depth with water (24 ± 1 ◦C). In there-test session, every animal was placed individually into theylinder for 15 min, 24 h prior to the 5 min swimming test. Salvialegans extract, imipramine and distilled water were adminis-ered three times: immediately after the initial 15-min pre-test,8 and 1 h prior to the swimming test. During the test session arained observer registered the immobility time, considered to be

M. Herrera-Ruiz et al. / Journal of Ethnopharmacology 107 (2006) 53–58 55

when the mouse made no further attempts to escape, apart fromthe movements necessary to keep its head above the water. It wassuggested (Porsolt et al., 1977) that the immobility reflected astate of lowered mood in which the animals had given up hope offinding an exit and had resigned themselves to the experimentalsituation.

2.6. Light–dark test (LDT)

The apparatus consisted of a Plexiglas box with two compart-ments (20 cm × 20 cm each), one of which was illuminated witha white light while the other remained dark. Each animal wasplaced at the center of the illuminated compartment, facing oneof the dark areas. The time spent in illuminated and dark places,as well as the number of entries in each space, was recorded for5 min (Crawley and Goodwin, 1980).

2.7. Open field test (OFT)

The open-field area was made of acrylic transparent walls andblack floor (30 cm × 30 cm × 15 cm) divided into nine squaresof equal area. The open field was used to evaluate the exploratoryactivity of the animal (Archer, 1973). The observed parameterswere the number of squares crossed (with the four paws) andnumber of rearings.

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Fig. 1. Effect produced by the oral administration of different doses of thehydroalcoholic extract from Salvia elegans on the time spend into the openarms (a), as well as, on the percentage of time spend and percentage of entriesinto the open arms (b) by mice exposed to the EPM test. *p < 0.05, **p < 0.001 onthe ANOVA followed by post hoc Dunnet test (mean ± S.D.). DZP = diazepam,PTX = picrotoxina, Veh = vehicle.

48.47 ± 25.5; 500 mg/kg, 46.3 ± 13; 1000 mg/kg, 40.2±15.6; 2000 mg/kg, 50.8 ± 6.5; F(5.59) = 14.434; p < 0.05;DZP 1.0 mg/kg, 53.7 ± 19; F(5.59) = 14.434; p < 0.001](Fig. 1b).

3.2. Light–dark test

The administration of different doses of Salvia ele-gans extract in ICR mice induced a significant incrementof the time spent by mice on the illuminated side of thelight–dark apparatus [Veh, 136 ± 15; 125 mg/kg, 157 ± 28;250 mg/kg, 166 ± 5; 500 mg/kg, 180 ± 21; 1000 mg/kg,167 ± 30; 2000 mg/kg, 173 ± 9; F(5.99) = 5.374; p < 0.05];similar to the effect observed in animals treated with DZP [Veh,136 ± 15; DZP 1.0 mg/kg, 195 ± 26; F(5.99) = 5.374; p < 0.001](Fig. 2).

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.8. Statistical analysis

The statistical analysis of the results was carried out withSPSS 11.0 program and based on an analysis of variance

ANOVA) followed by the Dunnet’s test, in which a significantifference was established among groups when the p value wasower than 0.05.

. Results

.1. Elevated plus-maze

The oral administration of different doses of Salvia elegansxtract in ICR mice exposed to the EPM test significantlyVeh 101.6 ± 31.0; 125 mg/kg, 137 ± 39.0; 250 mg/kg,18.53 ± 30.21; 2000 mg/kg, 153.0 ± 17.4; F(5.59) = 18.101;< 0.001] increased the time that mice spend in open armsomparing with the negative control (Fig. 1a). Further-ore, these results were not significantly different from

he group treated with diazepam [Veh, 101.6 ± 31.0; DZP.0 mg/kg, 178.0 ± 50; F(5.59) = 18.101; p < 0.05]. In thisodel, the animals that received PTX [2.0 mg/kg, 11.9 ± 40;(5.59) = 18.101; p < 0.05] showed a diminution of the activitynd the time spent in open arms. Compared with the negativeontrol group, the percentage of entries [Veh, 35.4 ± 7.1;25 mg/kg, 46.3 ± 14.5; 250 mg/kg, 46.7 ± 20.6; 500 mg/kg,6.0 ± 7; 1000 mg/kg, 49 ± 11.6; 2000 mg/kg, 55.8 ± 10;(5.59) = 16.506; p < 0.05; DZP 1.0 mg/kg, 59.5 ± 12.7;(5.59) = 16.506; p < 0.001] and the percentage of time spent

nto open arms were higher in mice treated with the extract andZP [Veh, 39.6 ± 10.6; 125 mg/kg, 46.6 ± 20.3; 250 mg/kg,

ig. 2. Effect produced by the oral administration of different doses of theydroalcoholic extract from Salvia elegans on the time spent by mice into thelluminated compartment on the light–dark test. *p < 0.05 with ANOVA followedy post hoc Dunnet test (mean ± S.D.). DZP = diazepam, Veh = vehicle.

56 M. Herrera-Ruiz et al. / Journal of Ethnopharmacology 107 (2006) 53–58

Fig. 3. Effect produced by the oral administration of different doses of thehydroalcoholic extract from Salvia elegans on the immobility time of ICRmice exposed to the the swimming forced paradigm. *p < 0.05, **p < 0.01 withANOVA followed by post hoc Dunnet test (mean ± S.D.). IMI = Imipramine,Veh = vehicle.

3.3. Forced swimming test

All doses of Salvia elegans extract administered in miceprovoked a significant [Veh 278 ± 6; 125 mg/kg, 154 ± 75;250 mg/kg, 166 ± 51; 500 mg/kg, 140 ± 80; 1000 mg/kg,190 ± 27; 2000 mg/kg, 156 ± 60; F(5.99) = 6.145; p < 0.05];diminution of immobility time when the animals were exposedto the FST. It is important to mention that IMI, the antidepressantused in the positive control group, induced a similar modificationto that observed with the plant extract [IMI 10 mg/kg, 80 ± 36;F(5.99) = 6.145, p < 0.05] (Fig. 3).

3.4. Open field test

The OFT was done in order to determine the effectof the administration of the plant extract upon sponta-neous motor activity. The total number of entries intoopen field was statistically similar in groups treated withthe vehicle and different doses of Salvia elegans extract[Veh 128 ± 46; 125 mg/kg, 145 ± 46; 250 mg/kg, 107 ± 17;500 mg/kg, 127 ± 55; 1000 mg/kg, 153 ± 55; 2000 mg/kg,121 ± 62; F(5.99) = 1.165; p > 0.05]. Animals treated with DZPshowed a light decrease on the number of entries; neverthe-less, it did not reach statistical significance [Veh 128 ± 46;DZP 1.0 mg/kg, 92 ± 32; F(5.99) = 1.165; p > 0.05] (Fig. 4).T

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250 mg/kg, 43 ± 13; 500 mg/kg, 46 ± 15; 1000 mg/kg, 48 ± 10;2000 mg/kg, 45 ± 19; F(5.99) = 3.634; p > 0.05] was only mod-ified in mice that received DZP which presented a significantdiminution of this parameter with respect to the control [Veh54 ± 13; DZP 1.0 mg/kg, 21.50 ± 13; F(5.99) = 3.634; p > 0.05].

4. Discussion

Despite the widely popular use of Salvia elegans for treat-ing nervous disorders, there is an absence of scientific reportsabout the evaluation of its pharmacological effects. In this work,it was demonstrated that the administration of different doses ofthe hydroalcoholic extract of Salvia elegans in mice was ableto induce anxiolytic effects, without modifying significantly thespontaneous motor activity. When the animals were exposed tothe EPM test, all mice were sensitive to the extract and showeda similar behavior to that of mice treated with DZP (there wereno statistical differences between these two groups). This ani-mal model is considered one of the most widely validated testsfor assaying sedative and anxiolytic substances such as the ben-zodiazepines (Pellow et al., 1985). The plant extract inducedanxiolytic effect beginning at the lower doses employed. Anincrease of the most important variables of the EPM test wasfound, as follows: the percentage of time that mice spend inthe open arms as well as the percentage of entries into thesealfidipdaTr

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he number or rearings [Veh 54 ± 13; 125 mg/kg, 47 ± 13;

ig. 4. Effect produced by the oral administration of different doses of hydroal-oholic extract from Salvia elegans on the total crossings and rearings numberf ICR mice exposed to the open field paradigm. *p < 0.05, **p < 0.01 withNOVA followed by post hoc Dunnet test (mean ± S.D.). DZP = diazepam,eh = vehicle.

rms. The anxiolytic effect was also evidenced through theight–dark test. As with the EPM test, this model is usefulor modeling anxiety, and it has been developed for predict-ng the potency of clinically used compounds for treating thisisease. It has been assumed that the time mice spend in thelluminated side of the box is the most useful and consistentarameter of anxiety (Young and Johnson, 1991). The lack ofose-dependent effect could be attributed to the biological vari-bility, as well as to the chemical complexity of the crude extract.hese factors, in statistical terms, turn out more dispersion of

esults.Regarding the medical treatment of psychiatric disorders, the

esults obtained in this work became important because notnly anxiolytic effects were observed; antidepressant activityas also shown. Results showed that the administration of thealvia elegans extract produced a diminution of immobility timef mice exposed to the forced swimming test. These behavioralffects were similar to that found by other authors after treatingice with classical antidepressant drugs as IMI (Porsolt et al.,

977; Borsini and Meli, 1988).The effects produced by Salvia elegans and DZP (1.0 mg/kg)

pon the open field test demonstrated that these products do notodify the spontaneous locomotor activity of mice, which indi-

ates that the plant extract exerts antidepressant and anxiolyticffects at different doses, without modifying significantly thisarameter. Therefore, it is probable that these effects are notelated to the stimulation of general motor activity (Novas et al.,988). Other authors have also reported that 1.0 mg/kg of DZPid not modify the spontaneous locomotor activity, neverthe-ess, higher doses decreased this parameter (Sousa et al., 2004;lodzinska et al., 2004).

M. Herrera-Ruiz et al. / Journal of Ethnopharmacology 107 (2006) 53–58 57

With the experimental test used in this work (which givesus information about motor activity, anxiety and depression)it is not possible to elucidate the action mechanism throughwhich Salvia elegans exerts both effects. Therefore, it is neces-sary to develop biochemical and pharmacological studies thatallow us to establish if the effects here reported are a con-sequence of the separate activation of nervous structures byone chemical compound by itself, or if the biological activ-ities are produced by different secondary metabolites of theplant.

Pharmacological studies have demonstrated that plants of theSalvia genus and some of their chemical constituents, includingessential oils and flavonoids, display nervous system depres-sor activities (Lu and Foo, 2002). For example, the flavonoidapigenin (Kavvadias et al., 2003), which selectively binds withhigh affinity to the central benzodiazepine receptor, possessesimportant anxiolytic (Salgueiro et al., 1997; Paladini et al., 1999)and antidepressant activities (Nakazawa et al., 2003). Salvia ele-gans contains linalool, an essential oil that exerts sedative effectsin humans (Kuroda et al., 2005). This species probably includeother compounds like apigenin, or others flavonoids with depres-sor nervous system activities.

Until now, there was just one pharmacological report aboutthe biological effects produced by Salvia elegans. That reportdemonstrated the ability of the methanolic extract to bind withcholinergic receptors on CNS of humans. Particularly, the extract

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